Research from a number of laboratories as well as our own has established that chronic treatment of rats with cholinesterase inhibitors causes a decrease in sensitivity of the smooth muscle of the ileum and atrium to cholinergic drugs. The decrease in muscle sensitivity is probably responsible for the tolerance which develops to this class of drugs. In the present studies experiments will be carried out to determine the association constant (KA) of the cholinergic drug carbachol in the longitudional smooth muscle of the rat ileum. If the decrease in sensitivity to carbachol which accompanies chronic cholinesterase inhibition involves an alteration in the cholinergic receptor this should be reflected by an altered KA. Tissues which show a decreased sensitivity to carbachol due to chronic cholinesterase inhibition will also be examined to determine if there are changes in cell membrane parameters such as transmembrane potential. Another aspect of this study will involve an electronmicroscopic examination of subsensitive smooth muscle.